Perinatal growth restriction is an independent risk factor for the development of hypertension. Once the environmental risk factors that contribute to cardiovascular risk are understood, underlying mechanisms can be identified and preventative strategies can be developed. In rat models, maternal undernutrition during lactation induces neonatal growth restriction, neonatal leptin deficiency, altered hypothalamic development, and obesity- related resistance to leptin-induced anorexia. While obesity is associated with resistance to the metabolic effects of leptin, emerging evidence suggest preserved leptin-dependent sympathetic signaling contributes to obesity-related hypertension. To explore the role of leptin in the neurodevelopmental origins of hypertension, we developed a novel non-interventional model in isogenic mice. Within our large breeding colony, we identified mice of average birth weight but with a weanling weight below the 10th percentile. Neonatal growth restriction led to profound neonatal leptin deficiency, reduced adult hypothalamic volumes, resting hypertension and increased sympathetic tone. Compared to control offspring, growth restricted mice had exaggerated pressor responses to central leptin administration and psychological stress. The stress-evoked hypertension was associated with hypothalamic activation and was abolished by central angiotensin II receptor blockade. We went on to show 1) central leptin administration elicits hypothalamic renin angiotensin system (RAS) activation and 2) leptin supplementation during incipient neonatal growth restriction blocks the programming of adult hypertension. Based on these data, we hypothesize that neonatal growth restriction-induced leptin deficiency programs adult hypertension through a persistent enhancement in central leptin and angiotensin II signaling. We will test the following hypotheses: I) Neonatal growth restriction enhances central leptin and angiotensin II signaling, particularly within the paraventricular nucleus of the hypothalamus; II) Neonatal leptin antagonist exposure induces adult hypertension in normally grown mice; and III) Neonatal leptin supplementation blocks the programming of adult hypertension by normalizing hypothalamic growth and central angiotensin II signaling. Our studies thus seek to identify: I) a novel interaction between leptin and the RAS in the regulation of arterial blood pressure, II) the molecular pathways that contribute to the expression of programmed hypertension; III) a neurotrophic factor deficiency that triggers adult hypertension, and IV) a hormonal replacement therapy that can be readily translated to the prevention of programmed hypertension. Our team is committed to understanding the effects of neonatal growth restriction on neurodevelopment, as we seek to develop novel interventions targeted to malleable windows of development that could transform our management of neonates at risk of developing life-long cardiovascular disease. PUBLIC HEALTH RELEVANCE: Neonatal growth restriction increases the risk of life-threatening cardiovascular disease. Once the underlying mechanisms are defined, preventative strategies can be developed. This proposal seeks to define strategies to optimize neonatal development and preserve cardiovascular health.